An age of genomically directed oncology has arrived, catalyzed by efforts to rationally design therapies targeting the molecular aberrations that promote individual tumor growth and progression. This has led to the prospective clinical sequencing of patients with active disease to guide their cancer care. Nevertheless, the utility of such prospective profiling is limited in many cancer types, perhaps most so in men with prostate cancer. In fact, due in part to their profound clinical and mutational heterogeneity, we know very little about how to therapeutically target the molecular lesions in the genomes that drive the emergence of the most aggressive metastatic castration-resistant prostate cancers (CRPC). We must address this urgent challenge to improve the survival of men with CRPC. We have recently shown that prospective clinical sequencing of active, advanced prostate cancers with linked clinical annotation can reveal both gene- and pathway-level genomic aberrations enriched in CRPC. We went on to show that both germline and somatic lesions targeting genes mediating homologous recombination (HR) were far more common in CRPC than even advanced castration-sensitive metastases. These findings underscore the potential therapeutic utility of defining the lesions that drive CRPC, but without a clinical-translational approach that tests these hypotheses clinically, the gap in our understanding will only widen. We propose to overcome this urgent clinical challenge by first developing and comprehensively analyzing a one-of-kind cohort of approximately 2,000 sequenced advanced prostate cancers from patients under active care with detailed clinical annotation, outcome, and treatment-response data. A major goal of this effort will be to identify alterations associated with progression to castration-resistance, a strategy that will facilitate the testing of novel approaches to treat such tumors. We will then assess the extent to which genomic loss of heterozygosity and related hallmarks of HR deficiency are correlated with different underlying somatic or germline HR/DNA repair genotypes, specific clinical variables, disease-specific progression, and outcome. Finally, we will clinically test the hypothesis that men with CRPCs bearing the hallmark of HR dysfunction, including those with germline or somatic BRCA mutations, derive clinical benefit from PARP inhibition. We will also seek to identify genomic aberrations that condition PARP inhibitor response and resistance in pre- and post-treatment samples and longitudinally collected tumor-derived cell-free DNA. Together, these studies seek to establish a translational genomic framework to facilitate effective, evidence-based precision oncology in men with CRPC by efficiently targeting essential pathways that drive the progression to advanced disease.